Upon the addition of certain exogenous factors known as mitogens, specific biochemical processes are triggered in a cell which result in the division of the cell into two new daughter cells. This process, subdivided into phases denoted G.sub.1, S, G.sub.2 and M, is known as the cell cycle. The first phase, G.sub.1, is a proliferative phase. This is directly followed by the S phase involving DNA synthesis, and finally the G.sub.2 /M phase during which the cell actually divides. This cycle is highly regulated and involves the orchestrated and ordered expression of a number of genes.
RhoG, a member of the Rho subfamily of small GTPases, is a protein whose transcription is induced within 12 hours of mitogen treatment. Furthermore, the degree of induction, as determined by mRNA level, is in direct proportion to the mitogen concentration administered. These data suggest that RhoG is necessary for entry into the DNA synthesis step (S phase) of the cell cycle which begins 14 hours after stimulation (Vincent et al., Mol. Cell. Biol., 1992, 12, 3138-3148).
In addition, all Rho proteins have been shown to affect the dynamic organization of the actin cytoskeleton whose regulation mediates many cellular processes. For example, changes occurring during cell cycle progression such as those associated with cell rounding and pinching off during mitosis are dependent on the appropriate assembly and disassembly of the cytoskeleton.
The involvement of RhoG in cell cycle progression and its reported role in pathways leading to actin polymerization suggests a link between RhoG and changes in cell shape during the cell cycle.
In NIH 3T3 cells, RhoG was shown to modulate the density to which the cells would grow. The conclusion drawn from this observation was that RhoG affects an actin-dependent signal transduction pathway mediating the level of contact inhibition through surface signals (Roux et al., Curr. Biol., 1997, 7, 629-637).
Finally, RhoG seems to play a role in the development of cancer. Cellular transformation and acquisition of the metastatic phenotype are the two main changes normal cells undergo during the progression to cancer. RhoG has been shown to participate in a signaling pathway involving ras-mediated transformation (Roux et al., Curr. Biol., 1997, 7, 629-637). In these studies it was shown that the activity of RhoG is required for cellular transformation.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of RhoG. To date, strategies aimed at inhibiting RhoG function have involved the use of bacterial enzymes such as the Clostridium botulinum C3 exoenzyme which ADP ribosylates the protein rendering it inactive or agents (natural enzyme inhibitors) to inhibit the posttranslational modification (isoprenylation) of RhoG (Narumiya and Morii, Cell Signal, 1993, 5, 9-19). However, these targeting strategies are not specific to RhoG, as many proteins undergo similar posttranslational modifications. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting RhoG function.